It has been proposed that the liver is metabolically zonated along the length of the circulation. In the extreme form of this concept, in the region where blood (oxygen and substrate rich) enters the liver, the periportal zone, the liver synthesizes glucose, while in the region from which the blood (oxygen and substrate poorer) leaves the liver, the perivenous zone, the liver breaks down glucose. The whole process has been termed intercellular futile cycling, since a major metabolic pathway is operating in opposing directions within the same organ. Our goal is to test whether such zonation actually exists in vivo (in the live animal) since previous evidence for this concept comes solely from in vitro studies, and can be considered only suggestive and highly speculative. Using radioactive tracers to label liver glycogen in vivo, we will then subsequently isolate and analyze the glycogen from the separate zones of the liver, which will allow us to characterize the degree of metabolic zonation of the liver. Since much of the in vitro evidence for liver zonation may depend on the oxygen gradient through the liver, we will also analyze the oxygen dependence of the actively biosynthetic pathways in hepatocyte and perfused liver systems. Liver hypoxia in various pathological states can lead to cellular damage and eventual death, and adaptation of the liver to nascent hypoxia, by slowing biosynthesis, can be a mechanism by which the hypoxia is kept from reaching too low a level in the effluent regions of the liver.